Regulation of Masking and Circadian Rhythm Phase

描述（由申请人提供）：负遮蔽是指哺乳动物暴露在光线下时夜间运动活动受到抑制。一方面，它被认为是昼夜节律评估的不便之处，因为它可以掩盖潜在的事件。另一方面，掩蔽本身已经被研究，并且已知是由介导光诱导相移的同类光感受器介导的。事实上，虽然光诱导掩蔽被认为与光诱导相移有根本的不同，但唯一能说明这个问题的数据来自两项视交叉上核（SCN）病变研究。更仔细的这些支持的观点，即SCN是必要的每一个反应，并通过外推，是起源两者。这一观点也与大量数据一致，这些数据表明光和运动活动可以相互抑制对昼夜节律的影响。该建议使用小鼠来解决昼夜节律视觉系统的两个基本问题。行为分析将允许比较毫秒级光刺激（数量、强度、闪光间隔）对掩蔽和相移的影响。通过类比论证来支持这两种反应受光调节相似的命题，因此，可能由相同的输入通路和视网膜受体核（SCN）控制。转基因小鼠（黑视素缺陷（Opn4-/-）和杆/锥变性（rd-/rd-））将用于消除各种光感受器的功能，并确定相同光感受器介导的掩蔽和相移的程度。他们还将确定iprgc是否是介导相移和掩蔽的SCN光接受途径的必要部分，即使这些细胞不含黑视素光色素。结论性研究将使用化学，刀切，病变和通道追踪方法来明确确定SCN是否介导相移和掩蔽，以及相同的大脑区域或通路是否参与光诱发睡眠现象。这一点尤其重要，因为到目前为止，还没有解剖学或生理学证据表明，光对掩蔽、相移或光诱发睡眠的影响可以在SCN细胞水平上加以区分。这些结果有望大大提高我们对光输入通路介导昼夜节律相移、掩蔽和光诱导睡眠的解剖学、生理学和功能的理解。使用极短（毫秒）的光刺激将为研究调节这三种行为的过程提供一种新的方法。生理和行为的昼夜节律通过涉及几种不同的光感受器类型的途径与光信号同步。该项目利用新颖的光刺激，新的测试程序和小鼠模型来辨别哪些光感受器，神经通路和大脑区域有助于节奏计时和光抑制运动和诱导睡眠的能力。研究还旨在促进对视觉健康和正常功能的基本了解。为了开发临床护理方法，治疗患有延迟睡眠综合征、季节性情感障碍、睡眠时间不适当或其他身体节律等问题的人，有必要了解光刺激如何作用和调节昼夜节律系统，以及它与睡眠和觉醒的关系。

DESCRIPTION (provided by applicant): Negative masking is the suppression of nocturnal locomotor activity that occurs when a mammal is exposed to light. On the one hand, it has been considered to be either an inconvenience for circadian rhythm assessment insofar as it can obscure underlying events. On the other, masking has been studied for its own sake and is known to be mediated by the same classes of photoreceptors that mediate light-induced phase shifts. In fact, although light-induced masking has been considered to be fundamentally different from light-induced phase shifts, the only data that actually speak to the issue come from two suprachiasmatic nucleus (SCN) lesion studies. The more careful of these supports the view that the SCN is necessary for each response and, by extrapolation, is the origin of both. This view is also consistent with substantial data showing that light and locomotor activity can mutually inhibit each other's effect on circadian phase. This proposal uses mice to address two issues fundamental to the circadian visual system. Behavioral analysis will allow comparison of the effects of millisecond light stimuli (number, intensity, inter-flash interval)on masking and phase shifts. An argument by analogy will be made in support of the proposition that these two responses are similarly modulated by light and, therefore, likely to be controlled by the same input pathway and retinorecipient nucleus (SCN). Transgenic mice (melanopsin deficient (Opn4-/-) and rod/cone degenerate (rd-/rd-)) will be used to eliminate function the various photoreceptors and determine the extent to which masking and phase shifts are mediated by the identical photoreceptors. They will also determine whether ipRGCs are a necessary part of the photoreception pathway to the SCN that mediates both phase shifts and masking, even if such cells do not contain melanopsin photopigment. Concluding studies will use a chemical, and knife cut, lesion and tract tracing methods to explicitly determine whether or not the SCN mediates both phase shifts and masking, and whether the same brain regions or pathways are involved in the phenomenon of light-induced sleep. This is particularly important because there is, as yet, no anatomical or physiological evidence that effects of light on masking, phase shifts or light-induced sleep can be distinguished at the level of SCN cells. The results are expected to greatly improve our understanding of the anatomy, physiology and function of the photic input pathway mediating circadian rhythm phase shifts, masking and light- induced sleep. The use of very brief (millisecond) photic stimuli will provide a novel approach for studying processes regulating those three behaviors. PUBLIC HEALTH RELEVANCE Physiological and behavioral circadian rhythms are synchronized to light signals by a pathway involving several different photoreceptor types. This project utilizes novel light stimuli, new test procedures and mouse models to discern which photoreceptors, neural pathways and brain regions contribute to rhythm timing and to the ability of light to suppress locomotion and induce sleep. Studies are also designed to promote basic understanding of visual health and normal function. In order to develop methods of clinical care for persons suffering from such problems as delayed phase sleep syndrome, seasonal affective disorder, inappropriate timing of sleep or other bodily rhythms, it is necessary to understand how photic stimuli act upon, and regulate, the circadian rhythm system, and how it relates to sleep and arousal.